1,720,978 research outputs found
The role of the MAP Kinase Signal Integrating Kinases in the proliferation and survival of cancer cells
No full textAdvances in chemotherapy and targeted systemic therapies for Urothelial cancer
No full textSystemic chemotherapy for cancer of the urothelial tract is used according to two main strategies. Neoadjuvant or adjuvant treatment combined with surgery and/or radiotherapy is aimed at cure of localised disease whilst treatment for advanced incurable disease allows for improved survival and palliation of symptoms. Cisplatin based combination regimens represent the standard of care in both of these settings and incorporation of gemcitabine has allowed for improvements in tolerability over older drugs. However, despite high objective response rates, impact on survival is modest. Targeted agents are now being incorporated into early phase clinical trials. These exciting new strategies hold promise for improved efficacy but with new challenges regarding toxicity profiles. This review will describe current evidence for the use of systemic chemotherapy for urothelial cancer and the state of the research evidence for use of the newer targeted agents
Late relapse (>2 years) on surveillance in stage I non-seminomatous germ cell tumours; predominant seminoma only histology
No full textObjectives: surveillance is a standard management approach following orchidectomy for stage I non-seminomatous and mixed germ cell tumours. Patients who relapse following this approach are treated with cisplatin-based chemotherapy, with retroperitoneal lymph node dissection considered for patients with post-chemotherapy residual masses.Patients and methods: we reviewed the clinicopathological data for all patients who relapse greater than 24 months after commencing our surveillance programme.Results: between 1989 and 2008, 453 patients with a median age of 30 years were entered into our surveillance program for stage I non-seminomatous germ cell tumours (NSGCTs) after orchidectomy alone. All primary tumour specimens contained NSGCT, with seminomatous elements identified in 168 cases (37%). One-hundred patients (22%) relapsed and the majority of relapses occurred within the first 2 years (76 ? 12 months, 15 ? 12 months ? 2 years). Nine patients relapsed after more than 2 years of surveillance. We found a high incidence of pure seminoma (56%) at sites of metastatic disease in this group. All late-relapsing patients were alive and disease free at a median follow up of 45 months from relapse.Conclusions: we recommend that late-relapsing patients with normal serum alpha fetoprotein levels undergo biopsy to define histologically the nature of recurrent disease. In those with pure seminoma retroperitoneal lymph node dissection for post chemotherapy residual masses can be avoide
The role of MNK proteins and eIF4E phosphorylation in breast cancer cell proliferation and survival
No full texteIF4E is over-expressed in many tumours, including a high proportion of breast cancers. eIF4E is an oncogene, and signalling pathways which promote eIF4E activity represent potential targets for therapeutic intervention in cancer. MNKs phosphorylate eIF4E on serine 209, a modification that can be required for eIF4E-dependent cell transformation. There is therefore a clear requirement to determine the role of MNKs in the proliferation and survival of cells from the major human tumours, such as breast cancer. Phosphorylated eIF4E protein was readily detectable in some breast tumour samples, but was below the limits of detection in others. Of 6 breast cancer cell lines representing the major sub-types of breast cancer, phosphorylated eIF4E was readily detectable in 5 of them, with MCF-7 cells displaying markedly lower levels. Long term colony forming assays demonstrated that all the five lines with high levels of phosphorylated eIF4E were highly sensitive to a MNK inhibitor. In short term assays, a range of responses was revealed. MCF-7 cells were insensitive in both assays. The anti-proliferative effects of the MNK inhibitor in breast cancer cells are primarily cytostatic, rather than cytotoxic, and are potentially due to the inhibition of cyclin D1 synthesis. Our data provide evidence that the sensitivity of breast cancer cells to MNK inhibition may correlate with baseline levels of eIF4E phosphorylation, and suggest that a proportion of breast cancers could be sensitive to inhibiting MNK kinase activity, and that the presence of phosphorylated eIF4E could provide a biomarker for the identification of responsive tumours.<br/
Clinical activity and safety of Pembrolizumab in Ipilimumab pre-treated patients with uveal melanoma
No full textBackground: Untreated metastatic uveal melanoma (“UM”) carries a grave prognosis. Unlike cutaneous melanoma (“CM”) there are no established treatments known to significantly improve outcomes for a meaningful proportion of patients. Inhibition of the PD1-PDL1 axis has shown promise in the management of cutaneous melanoma and we here report a two centre experience of UM patients receiving pembrolizumab.Methods: To assess the efficacy and safety of pembrolizumab we retrospectively analysed outcome data of 25 consecutive UM patients participating in the MK3475 expanded access programme who received pembrolizumab at 2mg/kg 3 weekly. Tumour assessment was evaluated using RECIST 1.1 and immune-related Response Criteria (“irRC”) by CT scanning. Toxicity was recorded utilising Common Terminology Criteria for Adverse Events (“CTCAE”) v4.03.Results: 25 patients were identified receiving a median of 6 cycles of treatment. Two patients achieved a partial response and 6 patients stable disease. After a median follow-up of 225 days median progression free survival was 91 days and overall survival was not reached. There was a significant trend for improved outcomes in patients with extrahepatic disease progression as opposed to liver only progression at the outset. 5 patients experienced grade 3 or 4 adverse events; there were no treatment related deaths.Conclusions: Pembrolizumab 2mg/kg q3w is a safe option in UM patients. Disease control rates, particularly in the subgroup of patients without progressive liver disease at the outset are promising; these results merit further investigation in clinical trials possibly incorporating liver targeted treatment modalities
Quality of life after melphalan percutaneous hepatic perfusion for patients with metastatic uveal melanoma
No full textBackground: recent studies indicate that melphalan percutaneous hepatic perfusion (M-PHP) for liver metastases from ocular melanoma (mUM) improves survival. Importantly, this benefit must be carefully balanced with changes in a patient's quality of life (QoL). This study examines the QoL changes post-M-PHP.Methods: retrospective analysis of the change in QoL using the Functional Assessment of Cancer Therapy-General (FACT-G) with mUM patients receiving M-PHP ( n = 20). The FACT-G scores, which comprise physical (PWB), social (SWB), emotional (EWB) and functional (FWB) wellbeing were measured pre-procedure and at day 1, day of discharge (mean = 2.4 days), 7, 14 and 28 days after M-PHP therapy. Wilcoxon signed-rank test gauged QoL domain changes.Results: baseline FACT-G median (IQR) scores were 101.8 (21.8). QoL scoring significantly decreased immediately after the procedure [day 1; 85 (27.5); P = 0.002] and gradually improved over time. By day 28, QoL almost returned to pre-procedure levels [100.3 (13.8); P = 0.31]. Subscore analysis revealed that the initial drop in QoL at day 1 post-procedure was attributable to the PWB (28 vs. 24; P = 0.001) and FWB domains (26 vs. 18.5; P < 0.001). By day 28 there was a statistically significant improvement in EWB ( P = 0.01).Conclusion: QoL following M-PHP decreases immediately after therapy and is not significantly different from baseline by the day of discharge. By day 28 there is improved emotional well-being. This study could help to optimize the time between treatment cycles when combined with toxicity data and blood count recovery.</p
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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